External Beam Radiation Therapy (EBRT) is used in the disease management of more than half of all cancer patients worldwide. In order to advance the field of EBRT and improve treatment outcomes, highly conformal, potent ablative doses must be delivered to maximize local tumor control and minimize toxicity to surrounding healthy tissue. Random and quasi-periodical anatomy motion during beam delivery poses a fundamental threat to realizing such conformity, and thus restricts the curative potential of EBRT. Existing and emerging technologies for localizing abdominal targets during beam delivery employ tracking of implanted fiducial markers, tracking of external surrogates, or guidance via magnetic resonance images. However, these technologies cannot provide real-time, volumetric, non-invasive, markerless soft-tissue image guidance capabilities to existing radiation delivery platforms. Thus a significant scientific and commercial opportunity exists to improve the technical capability and clinical outcomes of EBRT. Our vision is to realize this opportunity by pursuing a novel EBRT image guidance approach combining real-time volumetric (4D) ultrasound (US) with robotic technology. In the envisaged product, soft-tissue images of target anatomy are continuously obtained using a customized, minimally-invasive robotic manipulator designed to control the position and force of a 4D US probe against the patient. Before and during treatment, tissue displacements are tracked in spatially localized US images and used to guide precise patient positioning and EBRT delivery to the target. In this Phase I Small Business Technology Transfer grant, SoniTrack Systems proposes to establish the commercial feasibility of such a product by: (1) demonstrating the robustness of the robotic 4D US system for imaging abdominal and pelvic cancer patients; (2) demonstrating two effective strategies to account for image guidance system hardware in radiation treatment designs; and (3) demonstrating real-time 3D tracking of target sites with multi-plane and volumetric US imaging. Accomplishment of these objectives will remove the main technological and clinical risks related to the proposed product. Commercialization of the product by SoniTrack can transform the radiation therapy field by enabling treatments that are truly adaptive to the continuous changes of internal soft-tissue anatomy during radiation beam delivery.